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The cystic fibrosis F508del mutation in Crohn's disease
Journal of Cystic Fibrosis 10 (2011) 132 www.elsevier.com/locate/jcf
Correspondence The cystic fibrosis F508del mutation in Crohn's disease
Dear Sir, We read with much interest the recent study by Bahmanyar et al. [1], where they tested the hypothesis that heterozygous carriage of cystic fibrosis transmembrane conductance regulator (CFTR) mutations may have a protective effect on the risk of gastrointestinal (GI) diseases of the epithelial barrier, which include inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). From the analysis of a very large number of obligate carriers [parents and siblings of cystic fibrosis (CF) patients] and non-carriers, and the observation that GI diseases occur with similar frequencies in these two groups, the authors conclude by ruling out the existence of such protective effect. We previously tested the same hypothesis by measuring the occurrence of the most common CF mutation, F508del (accounting for 70% of CFTR mutant copies), in 2568 subjects from three independent cohorts of Italian, Swedish and Scottish IBD patients and controls [2]. In our study, F508del heterozygosity was significantly underrepresented both in Italian and Swedish CD patients compared to controls (0.3% vs 2.5% and 0% vs 1.6%, respectively), and it was absent in Scottish CD patients with colonic involvement. In particular, none of the 11 DeltaF508 heterozygous CD patients identified (1 Italian and 10 Scottish) had a clinical picture characterized by right-sided colitis. CFTR can induce NF-kB activation upon binding to lipopolysaccharide (LPS) from P. aeruginosa [3], and serves as epithelial receptor for S. Typhi transluminal migration [4]. Regional differences in the composition of the gut flora have been detected [5], and the inferred protective effect of F508del heterozygosity in colonic CD may therefore come through similar interactions with yet unidentified site-specific residing bacteria.
Although recruited through different study settings, Bahmanyar et al. identified 7 CD patients out of 2930 CF obligate heteroygotes in their survey. While larger numbers of CF heterozygous CD cases would be required to draw definitive conclusions, it would be interesting to know both the nature of the CFTR mutation and the site of intestinal damage in these 7 patients, before rejecting our common hypothesis. References [1] Bahmanyar S, Ekbom A, Askling J, Johannesson M, Montgomery SM. Cystic fibrosis gene mutations and gastrointestinal diseases. J Cyst Fibros 2010;9:288–91. [2] Bresso F, Askling J, Astegiano M, et al. Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease. Inflamm Bowel Dis 2007;13:531–6. [3] Schroeder TH, Lee MM, Yacono PW, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci USA 2002;99:6907–12. [4] Pier GB, Grout M, Zaidi T, et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998;393:79–82. [5] Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635–8.
Francesca Bresso Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Department of Medicine, Karolinska Institutet, Stockholm, Sweden Mauro D'Amato Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Corresponding author. Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovag 7-9, 14183, Stockholm, Sweden. Tel.: +46 8 6089143; fax: + 46 8 7745538. E-mail address: [email protected].
1569-1993/$ - see front matter © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2010.10.006
Correspondence The cystic fibrosis F508del mutation in Crohn's disease
Dear Sir, We read with much interest the recent study by Bahmanyar et al. [1], where they tested the hypothesis that heterozygous carriage of cystic fibrosis transmembrane conductance regulator (CFTR) mutations may have a protective effect on the risk of gastrointestinal (GI) diseases of the epithelial barrier, which include inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). From the analysis of a very large number of obligate carriers [parents and siblings of cystic fibrosis (CF) patients] and non-carriers, and the observation that GI diseases occur with similar frequencies in these two groups, the authors conclude by ruling out the existence of such protective effect. We previously tested the same hypothesis by measuring the occurrence of the most common CF mutation, F508del (accounting for 70% of CFTR mutant copies), in 2568 subjects from three independent cohorts of Italian, Swedish and Scottish IBD patients and controls [2]. In our study, F508del heterozygosity was significantly underrepresented both in Italian and Swedish CD patients compared to controls (0.3% vs 2.5% and 0% vs 1.6%, respectively), and it was absent in Scottish CD patients with colonic involvement. In particular, none of the 11 DeltaF508 heterozygous CD patients identified (1 Italian and 10 Scottish) had a clinical picture characterized by right-sided colitis. CFTR can induce NF-kB activation upon binding to lipopolysaccharide (LPS) from P. aeruginosa [3], and serves as epithelial receptor for S. Typhi transluminal migration [4]. Regional differences in the composition of the gut flora have been detected [5], and the inferred protective effect of F508del heterozygosity in colonic CD may therefore come through similar interactions with yet unidentified site-specific residing bacteria.
Although recruited through different study settings, Bahmanyar et al. identified 7 CD patients out of 2930 CF obligate heteroygotes in their survey. While larger numbers of CF heterozygous CD cases would be required to draw definitive conclusions, it would be interesting to know both the nature of the CFTR mutation and the site of intestinal damage in these 7 patients, before rejecting our common hypothesis. References [1] Bahmanyar S, Ekbom A, Askling J, Johannesson M, Montgomery SM. Cystic fibrosis gene mutations and gastrointestinal diseases. J Cyst Fibros 2010;9:288–91. [2] Bresso F, Askling J, Astegiano M, et al. Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease. Inflamm Bowel Dis 2007;13:531–6. [3] Schroeder TH, Lee MM, Yacono PW, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci USA 2002;99:6907–12. [4] Pier GB, Grout M, Zaidi T, et al. Salmonella typhi uses CFTR to enter intestinal epithelial cells. Nature 1998;393:79–82. [5] Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005;308:1635–8.
Francesca Bresso Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Department of Medicine, Karolinska Institutet, Stockholm, Sweden Mauro D'Amato Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden Corresponding author. Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovag 7-9, 14183, Stockholm, Sweden. Tel.: +46 8 6089143; fax: + 46 8 7745538. E-mail address: [email protected].
1569-1993/$ - see front matter © 2010 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jcf.2010.10.006